Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.

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Anovel antibiotic, GE2270A, was isolated from the fermentation broth of a strain of Planobispora rosea. The product was found to inhibit bacterial protein synthesis. Structural characteristics showed similarities between GE2270 A and thiazolyl peptides such as micrococcin which is known to inhibit protein synthesis by acting directly on the ribosome. Despite this similarity GE2270A showed functional analogy to kirromycin-like antibiotics and pulvomycin, as its molecular target was found to be elongation factor Tu (EF-Tu). GE2270A is active against Gram-positive microorganism and anaerobes and differs from the other EF-Tu inhibitors in its spectrum of antimicrobial activity. 693 GE2270A, a novel peptide antibiotic, emerged from a screening program designed to detect inhibitors of protein synthesis. The present paper deals with the discovery, isolation, initial physico-chemical and biological characterization of this antibiotic. Materials and Methods Cultural and Growth Characteristics of the Producing Strain Colonial and morphological characters were determined with standard methods1'2*. Color determination was madeaccording to Maerz and Paul3). Growthon sole sources of carbon was determined after incubation at 28°C for 2 weeks1*. Chemotaxonomic Characteristics of the Producing Strain Freeze-dried biomass was examined to determine the major chemotaxonomiccharacteristics. Cell wall diamino acids were determined by TLCby a modification of the method of Becker et a/.4)5). Wholecell sugars were hydrolyzed, reduced and derivatized. The resultant alditol acetates were analyzed by GC6). Fatty acid methyl esters were similarly analyzed by GC7). Menaquinones and polar lipids were extracted and analyzed by HPLCand 2D TLC, respectively8*. Fermentation of the Producing Strain A 500-ml Erlenmeyer flask containing 100 ml of seed medium (Pdlypeptone 0.5%, yeast extract 0.3%, beef extract 0.2%, soybean meal 0.2%, starch 2%, calcium carbonate 1%, pH 7.0) was inoculated from an oatmeal slant of the producing strain. After incubation at 28°C for 96 hours on a rotary shaker (200 rpm), the biomass was transferred to a 10-liter jar fermenter containing 4 liters of the seed medium. This culture was grown for 72 hours at 28°C with 2 liters/minute air flow and stirring at 900rpm, prior to inoculating a jar fermenter containing 50 liters of production medium(starch 2%, peptone 0.25%,

The mtDNAs of 235 individuals from five ethnic groups were analyzed for restriction site variation by digestion with restriction endonuclease Hpa I, Southern transfer, and hybridization with 32P-labeled human mtDNA. Six different cleavage patterns (morphs) were found, all of which could be related to each other by single nucleotide substitutions. Differences were found in the frequency of these morphs among the populations.

In the course of a search for glycopeptide antibiotics having novel biological properties, we isolated A40926. Produced by an actinomycete of the genus Actinomadura, A40926 is a complex of four main factors which contain a fatty acid as part of a glycolipid attached to the peptide backbone. Its activity was, in most respects, similar to that of other glycopeptides, such as vancomycin and teicoplanin. However, in addition to inhibiting gram-positive bacteria, A40926 was very active against Neisseria gonorrhoeae. A40926 was rapidly bactericidal for N. gonorrhoeae clinical isolates at concentrations equal to or slightly higher than the MIC. In mice, levels in serum were higher and more prolonged than those of an equivalent subcutaneous dose of teicoplanin. These properties suggest that A40926 may have potential in the therapy of gonorrhea.The increased frequency of isolation of multiply antibioticresistant gram-positive bacteria has led to wider use of antibacterial agents which were originally rarely considered for first-line therapy, such as the glycopeptide vancomycin (18). One of the advantages of this antibiotic is that, thus far, resistance is rare and restricted to certain coagulase-negative staphylococci (25). The success of vancomycin has stimulated the development of new glycopeptides, such as teicoplanin (5,13,32,33). These antibiotics inhibit cell wall biosynthesis by binding to the D-alanyl-D-alanine portion of nascent peptidoglycan (22). Specific binding to an affinity resin containing acyl-D-alanyl-D-alanine groups (9) formed the basis of our search for new glycopeptides.Among the new glycopeptides identified, we focused our attention on those having novel biological properties. A40926 is the most interesting antibiotic which has emerged thus far from our screening campaign. In fermentation broths, we found it as a complex of four factors (PA, PB, A, and B). PA and PB, described here for the first time, predominated in the broth; during purification, these two compounds were largely converted to A and B, whose structures have been described recently (31a). One feature of all four factors, which relates them to teicoplanin and some other glycopeptides (aridicins and kibdellins) (3, 27, 12) while distinguishing them from vancomycin, ristocetin, and others, is the presence of a fatty acid moiety attached to one of the sugars. In terms of biological activity, the most striking difference between the components of the A40926 complex and other glycopeptide antibiotics is their activity against Neisseria gonorrhoeae.MATERIALS AND METHODS Isolation of A40926. We screened specifically for glycopeptide antibiotics by passing fermentation broths over the affinity resin Sepharose-D-alanyl-D-alanine (9) and eluting adsorbed glycopeptides with 1% aqueous ammonia. The strain producing A40926 was found in a soil sample collected in India. Batch adsorption to the same affinity resin described above yielded nearly pure A40926 complex in one step. Quick neutralization of the ammonia eluate yielded primarily the two fac...